This proposal brings together investigators from around the world to carry out a genetic study of severe major depressive disorder (MDD) treated with electroconvulsive therapy (ECT). These individuals are among the most severely ill people seen by psychiatrists, and we anticipate that genetic studies will have greater power. The driving goals of the proposal are to identify genetic variation that 1) is associated with severe MDD and indicate which patients are candidates for ECT, and 2) influence response to ECT and predict which patients may benefit from treatment. MDD is a leading cause of disability worldwide, and up to a third of patients do not respond to first line therapies. The search to find the right treatment may require a lengthy period of trial and error with multiple treatments during which patients continue to suffer and remain at elevated risk for adverse outcomes, including suicide. ECT is one of the more effective treatments for severe MDD that is refractory to first line therapies. However, even with ECT between one-third to one-half of patients fail to achieve remission after acute treatment, and cognitive impairments may emerge that limit its wider use. It is clear genetic factors contribute to risk for MDD, and recent studies genome-wide association studies (GWAS) have identified >100 susceptibility loci. However, MDD is a heterogeneous condition, and most of the cases in the previous GWAS were of lesser severity. Studies have shown that severe/treatment refractory MDD is a more heritable sub-type, highlighting the potential benefit of focusing on severe MDD by studying those treated with ECT. Moreover, there is evidence that genetic factors may shape clinical response to ECT, but this has not been studied genome-wide with sufficient sample sizes. To address these limitations, the Genetics of ECT Consortium (GenECT, a PGC MDD subgroup) has brought together ECT centers globally, including those in the National Network of Depression Centers (NNDC) in the US, to carry out a genetic study with the following aims: 1) ascertain, broadly consent, consistently phenotype, and biosample 25,000 patients with severe MDD treated by ECT; 2) conduct a GWAS against age, sex and ancestry matched controls to identify genetic variants that contribute to risk for severe MDD; and 3) conduct a GWAS of clinical response to ECT in a sub-sample of 10,000 cases with prospective follow-up data to identify genetic variants associated with changes in measures of MDD or occurrence of cognitive impairments. This proposal will advance our understanding of the genetic etiology of severe MDD which, in turn, will motivate the development of new and more effective treatment strategies for this burdensome and difficult to treat condition. In addition, it will identify genetic factors that can help distinguish which patients are good candidates for ECT even before initiating treatment.